A distinctive class of pulmonary small-granule epithelial cell (SGC) with morphologic and histochemical features of APUD polypeptide hormone-producing cells has been described in numerous vertebrates. In the extrapulmonary airways these cells occur singly, while in the intrapulmonary they occur either singly or in clusters, frequently associated with nerve fibers and/or endings. At present, however, the functional role(s) of these cells in (are) not well understood, but by analogy with the carotid and aortic bodies they may serve as intrapulmonary chemoreceptors regulating ventilation and perfusion. Accordingly, it has been demonstrated that hypoxia, atmospheres containing lowered PO2, results in a release of the secretory vesicles from these cells. However, insofar as decreased airway PO2 also results in a simultaneous decrease in arterial and tissue PO2, the stimulus whereby these cells release their secretory vesicles remains to be elucidated. Such knowledge is essential for any putative chemoreceptor function, for any internal organ in ultimately dependent upon oxidative metabolism and will demonstrate morphologic alterations to reduced oxygen. Therefore, the primary focus of this proposal will be directed towards characterizing the mechanism by which clustered pulmonary SGCs respond to hypoxia as they appear and mature in the intact respiratory system during fetal, neonatal as they appear and mature in the intact respiratory system during fetal, neonatal and adult life. This will be accomplished by exposing animals to: (1) atmospheres containing lowered PO2 resulting in a decreased airway and arterial PO2 (hypoxic hypoxia), or (2) atmospheres containing carbon monoxide resulting in essentially normal airway and arterial PO2 but decreased tissue O2 (tissue hypoxia). Exocytosis of the secretory vesicles will be examined by qualitative and quantitative electron microscopic techniques. additionally, the experimental design will also examine if and when the cells "functionally" mature in their response to decreased airway or tissue PO2. Finally, similar ultrastructural and morphometric techniques will be utilized to establish dose-response curves for airway and/or tissue hypoxia. Accordingly, the proposed studies will enable us to assess the role or roles of these clustered cells and aid in our understanding of the normal controlling mechanisms of the lung.